Enhancer Activation, Release and Retargeting in Transcription

This dissertation, by Soohwan Oh, discusses the general mechanisms how enhancers bring target genes activation in various stimuli. Enhancers are cis-regulatory DNA sequences that can increase the transcription of its cognate target genes. Fine-tuned coordination between enhancers and promoters is a fundamental tenant of gene transcriptional control. While enhancer-promoter (E-P) looping is widely observed, the precise mechanism allowing enhancer-promoter inter-regulation via the loop remains unknown. Here we report two interesting findings of 1) enhancer activation and 2) enhancer-promoter specificity. Critical chromatin structure regulators Condensin Complex I and II exhibit an unexpected, dramatic estrogen-induced recruitment to estrogen receptor a (ER-a)-bound eRNA transcribing active enhancers in interphase breast cancer cells and play essential roles in modulating estrogen-regulated enhancer activation and coding gene transcriptional program. (see Chapter 1). In addition, we found genetic deletion or mutation of gene promoters often, surprisingly, results in a more active state of their cognate enhancers. Intriguingly, the super-active enhancers switch their promoter target, causing other genes in the same contact domain to be activated, a target switching process that we referred to as “enhancer release and retargeting” (ERR). Integrative analyses of cancer mutations, the GTEx database and disease risk loci elucidated that ERR events represent a remarkably common, if overlooked, mechanism underlying disease-associated gene activation. (see Chapter 2